Although effective vaccines for a variety of human viruses were developed by an empirical, trial-and-error approach without knowledge of the mechanisms or requirements for protective immunity, HIV-1 is different. HIV-1 is unlike any viral pathogen that we have faced previously. The principal problem lies in HIV's uncanny ability to avoid host immune defenses and to replicate continuously in the face of apparently-strong host immune responses. In the absence of blind luck in stumbling upon a successful vaccine for HIV-1, it is likely that we will need to solve specific scientific obstacles to guide our way. First and foremost, we must learn what is needed from a vaccine in order to achieve effective protective immunity. The experiments proposed in this component of the program project are directed at elucidating the relative contribution of anti- Env immune responses, particularly neutralizing antibody responses, to the remarkable protection conferred by live-attenuated SIV. The principal approach to be used is a genetic one: immunized rhesus macaques will be challenged with cloned pathogenic SIVs that are matched or mismatched in particular regions of the genome relative to the sequences present in the vaccine strain. To what extent does a mismatch of Env sequences decrease the degree of protection that is observed? To what extent does a mismatch of all non- Env sequences decrease the degree of protection that is observed? Vaccine/challenge experiments in Project 2 will also employ experimental designs by which rhesus macaques control the SIV vaccine strain in the absence of detectable anti-SIV antibody responses. These systems will be used to investigate whether viral-specific antibody responses are important for the degree of protection against homologous SIV239 challenge. Defining the relative contribution of anti-Env responses to the degree of protection is not a simple, trivial point of academic interest. Vaccine approaches are currently advancing through human testing without an Envelope component despite the fact that we simply do not know how important anti-Env responses may be for the degree of protection that can be achieved. The outcomes of the vaccine/challenge experiments in Project 2 will provide important guidance on the logic of including, or omitting, Envelope components for vaccine approaches being tested in people.